rs876660134

Positions:

• chr11-108312466-AAAAGT-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000051.4(ATM):​c.5979_5983del​(p.Ser1993ArgfsTer23) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,438,028 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 8.65

Genes affected

ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108312466-AAAAGT-A is Pathogenic according to our data. Variant chr11-108312466-AAAAGT-A is described in ClinVar as [Pathogenic]. Clinvar id is 233016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.5979_5983del	p.Ser1993ArgfsTer23	frameshift_variant	40/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.5979_5983del	p.Ser1993ArgfsTer23	frameshift_variant	40/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251034 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135776

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1438028 Hom.: 0 AF XY: 0.00000140 AC XY: 1 AN XY: 716804

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 25, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 12, 2022	Variant summary: ATM c.5979_5983delTAAAG (p.Ser1993ArgfsX23) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8e-06 in 251034 control chromosomes (gnomAD). c.5979_5983delTAAAG (aka. 5979del5 or 5979delTAAAG) has been reported in the literature in several compound heterozygous individuals affected with Ataxia-Telangiectasia (Gilad_1996, Cavalieri_2006, Magliozzi_2006, Du_2008, Chessa_2009). These data indicate that the variant is likely to be associated with disease. In addition, the variant was also reported in heterozygous state in individuals affected with breast cancer, but was also found in controls (e.g. Droling_2021, via LOVD). At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated lack of the protein product in patient derived cells from a compound heterozygous patient, who carried a truncating variant in trans (Prodosmo_2013). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change creates a premature translational stop signal (p.Ser1993Argfs*23) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (rs749049519, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with ataxia-telangectasia (PMID: 8845835, 17124347, 17910737, 19691550, 23454770). This variant is also known as 5979del5 or 5979delTAAAG. ClinVar contains an entry for this variant (Variation ID: 233016). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 19, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 09, 2023	This variant, also referred to as 5979delTAAAG or 5979del5, deletes 5 nucleotides in exon 40 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in the compound heterozygous state in individuals affected with autosomal recessive ataxia-telangiectasia (PMID: 8845835, 17124347, 17910737, 19691550, 23454770), indicating that this variant contributes to disease. This variant has also been observed in individuals affected with breast cancer (PMID: 28779002), colorectal cancer (PMID: 34761457), or melanoma (PMID: 32325837). This variant has been identified in 2/251034 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 22, 2023	The c.5979_5983delTAAAG pathogenic mutation, located in coding exon 39 of the ATM gene, results from a deletion of 5 nucleotides at nucleotide positions 5979 to 5983, causing a translational frameshift with a predicted alternate stop codon (p.S1993Rfs*23). This mutation was first reported in conjunction with a second truncating ATM mutation in an Italian patient with classic ataxia-telangiectasia (Gilad S et al. Hum. Mol. Genet. 1996 Apr; 5(4):433-9). Additionally, this alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals from the United Kingdom and in an individual referred for next generation sequencing based on personal and/or family history from Greece, Romania or Turkey (Decker B et al. J. Med. Genet. 2017 11;54:732-741; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This variant is a five base pair deletion from exon 40 of the ATM mRNA, causing a frameshift after codon 1993 and this creates a premature translational stop signal 23 amino acid residues later. This is expected to result in an absent or disrupted protein product. Truncating variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is also known as 5979del5 or 5979delTAAAG in the literature and has been described in several individuals affected with ataxia-telangectasia (PMID: 8845835, 17124347, 17910737, 19691550, 23454770) and in individuals undergoing panel testing for hereditary syndrome (PMID: 31159747). The mutation database ClinVar contains entries for this variant (Variation ID: 233016). -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jan 26, 2024

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs876660134; hg19: chr11-108183193;